The main purpose of this proposal is to define the variability in virulence among HIV-1 isolates from individuals with widely divergent progression rates and to assess the interrelationships between virus burden, phenotype, and the capacity to induce immune activation/apoptosis, in a SCID-hu mouse model. AIM 1 is to continue to determine the relationship between virus burden, markers of immune activation/apoptosis and CD4 decline in longitudinal studies of highly characterized LTNP and RP from the SFMHS. Parallel studies of quasispecies diversity, the in vitro phenotype of virus isolates, and various immune responses are being conducted with these subjects under other funding. AIM 2 is to further assess the importance of viral diversity by characterizing the phenotypic behavior of HIV-1 isolates from LTNP and NP (10 each) in an improved SCID mouse model. Measurements to be made in mice include: 1) thymic and/or peripheral CD4+ cell loss 2) plasma viral RNA and 3) level of various markers of immune activation and apoptosis.